Evidence That Patients With Single Versus Recurrent Depressive Episodes Are Differentially Sensitive to Treatment Discontinuation: A Meta-Analysis of Placebo-Controlled Randomized Trials

Background: Antidepressants are effective in the prevention of relapse after remission from an acute depressive episode. It is unclear, however, to what degree duration of the continuation phase, level of abruptness of antidepressant discontinuation, or the number of previous episodes moderate the prophylactic effect of antidepressants.

Data Sources: Searches were conducted to identify all published randomized, placebo-controlled, double-blind clinical trials available for review by May 2007 on the efficacy of continuation or maintenance treatment of major depressive disorder with either selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) that included patients entering a maintenance phase after achieving remission from the acute phase. The MEDLINE and EMBASE databases were searched using the terms depression, antidepressants, discontinuation, and maintenance treatment; this was followed by reference checks of articles thus identified. In addition, the Cochrane Library was also searched using the same terms. Some authors of the identified papers were contacted for specific data.

Data Synthesis: Data were collected from 30 trials with 4890 participating patients. The overall reduction of relapse risk in the maintenance phase was highly significant for both SSRIs (OR = 0.24, 95% CI = 0.20 to 0.29) and TCAs (OR = 0.29, 95% CI = 0.23 to 0.38) over 1 year of follow-up of maintenance treatment. The prophylactic effect appeared to be constant over the length of the continuation phase. Recurrent episode patients experienced less protection from antidepressants over the maintenance phase (OR = 0.37, 95% CI = 0.31 to 0.44) than single episode patients (OR = 0.12, 95% CI = 0.06 to 0.26).

Conclusions: Antidepressants robustly reduce relapse risk in the maintenance phase, regardless of a number of clinical and pharmacologic factors. There is evidence, however, that with increasing number of episodes, patients develop a relative resistance against the prophylactic properties of antidepressant medication.